Inherited Neurological Diseases and Disorders of Myelin

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Introduction

The history of clinical description of genetically inherited white matter diseases is long. More than 100years ago the pathological description of Pelizaeus-Merzbacher disease started the history of leukodystrophies, followed by a description of metachromatic leukodystrophy and Krabbe disease.

The original term of leukodystrophy has been changed to leukoencephalopathy to better cover the group of diseases. This term better describes the group of diseases that not only include loss of previously formed myelin, but also hypomyelination (delay in normal myelination process) and failure to myelinate at all or failure to maintain normal myelination, such as destruction of myelin. In the past 10years our understanding of the diseases has increased and simultaneously new leukoencephalopathy syndromes have been defined. In spite of all the genetic, biochemical marker and imaging advances, a significant number of white matter leukoencephalopathy syndromes remain without specific diagnosis.

Our prospective has broadened with the new discov- eries associated with CNS involvement, such as defects in genes coding for protein that are not typically associated with myelin sheath that can cause myelin disorders.

CT and later MR imaging markedly changed our concept of white matter abnormalities. New imaging techniques such as DW imaging, ADC maps and proton and phosphorus MRS have helped further to characterize the leukoencephalopathies.

MRI imaging has become a routine clinical tool for the evaluation of brain maturation and myelination in young children. The maturation and decrease in brain water content and increase in macromolecules such as myelin reﬂects signal intensity changes in standard T1- and T2-weighted images. The maturation process can also cause alterations in brain water diffusion that can be seen and analyzed quantitative-

ly with diffusion tensor (DT) imaging. DT imaging characterizes the 3D spatial distribution of water diffusion in each MRI voxel.

The ﬁrst DT imaging studies in human brain maturation were performed on preterm and term neonates and revealed that the isotropic diffusion co- efﬁcient decreases and the diffusion anisotropy in- creases with increasing gestational age. This tech- nique was later applied to normal brain development in children. From normal brain development the use of DT imaging has been expanded in pathological CNS conditions. DT imaging has been used as an early indicator of white matter demyelination and to monitor the severity of the white matter change before it is seen in conventional MR sequences. Use of more sophisticated techniques will generate new op- portunities to provide clinically useful information early in the disease process and detect CNS dysfunction that have been previously been considered be- yond the capabilities of routine imaging techniques.

Suggested Reading

Engelbrecht V, Scherer A, Rassek M, Witsack HJ, Modder U (2002) Diffusion-weighted MR imaging in the brain in children: ﬁndings in the normal brain and in the brain with white matter diseases. Radiology 222:410–418 Holland BA, Haas DK, Norman D, Brant-Zawadzki M, Newton

TH (1986) MRI of normal brain maturation. AJNR Am J Neuroradiol 7:201–208

Kreis R, Hofmann L, Kuhlmann B, Boesch C, Bossi E, Huppi PS (2002) Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 48:

949–958

Mukherjee P, Miller JH, Shimony JS, et al (2002) Diffusion-tensor MR imaging of gray and white matter development during normal human brain maturation. AJNR Am J Neu- roradiol 23:1445–1456

Schneider JF, Il’yasov KA, Boltshauser E, Hennig J, Martin E (2003) Diffusion tensor imaging in cases of adrenoleukodystrophy: preliminary experience as a marker for early demyelination? AJNR Am J Neuroradiol 24:819–824

Inherited Neurological Diseases and Disorders of Myelin

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Hereditary Myelin Disorders Krabbe’s Disease

(Globoid Cell Leukodystrophy)

Infantile Type with Progression Over Time and Cerebellar Involvement

Clinical Presentation

A ﬂoppy female infant with irritability and hyperacu- sis. She had also feeding difﬁculties.

Images (Fig. 3.1)

A. T2-weighted (conventional SE) image at the age of 12months shows nonspeciﬁc hyperintensity around the frontal horns, atria and putamen. Al- though CT at the age of 11months did not demonstrate calciﬁcation, the globus pallidus low signal can be related to mineral accumulation

B. T2-weighted image at the age of 13months demonstrates increased low signal in the globus pal- lidi and thalami (arrows). The corpus callosum and frontal white matter myelination have progressed at the same time with increase in hyperintensity at the posterior limb of the internal capsule C. T2-weighted image at the age of 22months. There is severe loss of hemispheric white matter with abnormal hyperintensity and deep sulci. An abnormal high signal is seen in both pulvinar regions, the posterior limb of internal capsules and insular cortices. Hyperintensity in the anterior thalamic and lentiform nucleus have progressed with decreased volume of the gray nuclei. At the same time the patient stopped interacting with her envi- ronment

D. Coronal T2-weighted image at the age of 32months.

The white matter hyperintensity has progressed signiﬁcantly and now also the cerebellar white matter is hyperintense. There is diffuse volume loss

Figure 3.1

Krabbe’s disease, infantile type with progression over time and cerebellar involvement

A B

C D

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Infantile Type with Delayed Myelination Clinical Presentation

A 3-month-old male with irritability.

A. Axial T2-weighted image at the age of 3months shows prominence of sylvian ﬁssures and cortical sulci

B. Coronal T2-weighted image at the age of 3months reveals mild prominence of cortical CSF spaces

Figure 3.2

Krabbe’s disease, infantile type with delayed myelination

A B C

D E F

G

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C. Axial T2-weighted image through the centrum semiovale shows nonmyelinated white matter D. Axial T2-weighted image at the age of 6months re-

veals hyperintensity on the posterior limb of internal capsules that normally are myelinated at this age (arrows). Abnormal white matter hyperinten- sity is also seen behind the trigones. Diffuse volume loss has progressed

E. Coronal T2 image at the age of 6months shows progression of the periventricular white matter hyperintensity. Diffuse atrophy has progressed with dilated ventricles and sulci. Hippocampi are atrophic

F. Coronal T2-weighted image posterior to the image shown in E reveals progression of the periventricular and internal capsule white matter hyperintensity. The diffuse atrophy is well seen by progressive ventricular dilatation

G. At the age of 6months the global volume loss has progressed. White matter volume has decreased and hyperintensity has also progressed

Infantile Type with Caudate Calciﬁcation Clinical Presentation

A 6-month-old female infant with irritability, spasticity and blindness

Image (Fig. 3.3)

A. Noncontrast CT scan shows thalamic and caudate body calciﬁcation (arrow). Mild periventricular hypodensity is seen

Discussion

Krabbe’s disease is a neurodegenerative disease characterized by severe destruction of myelin and the presence of globoid bodies in the white matter. The biochemical defect is marked by deficiency of lysosomal enzyme, galactosylceramidase, resulting in accumulation of galactocerebroside. It is an autosomal recessive childhood disorder with the gene localized at chromosome 14. Krabbe’s disease is classically divided into three groups: early infantile, late infantile and juvenile forms. Others have simplified the classification into “infantile” and “late onset”. The infantile form is the most common subtype and generally

presents with progressive irritability, vision loss, hy- peracusis and rapid motor or mental decline and death usually occurs by 2years of age. The late onset type presents after 10years of age and mimics a peripheral neuropathy.

MR imaging demonstrates diffuse abnormalities of the white matter, which may be difﬁcult to appreciate at the very early stage, when the nonmyelinated white matter is still normally hyperintense on T2- weighted images. CT imaging may be more helpful in the initial stages and shows symmetrically increased attenuation within the basal ganglia, thalami, and centrum semiovale. Progressive cerebral and cerebellar atrophy are seen in the late stage of the disease.

Pyramidal tract involvement is the characteristic feature of the disease. In late onset disease, a hyperintense signal may be seen in the white matter, mostly in the posterior regions, with frequent involvement of the splenium of the corpus callosum.

MR spectroscopy reveals prominent peaks from choline-containing areas with high creatine and in- ositol peaks. The NAA peak is markedly reduced and the choline to NAA ratio is abnormally high. The lactic acid peak may be seen in some cases. This constel- lation MR spectroscopy ﬁnding is seen of extensive demyelination, gliosis, and loss of axons in the involved white matter. The latter two events occur in the later stages of Krabbe’s disease.

Figure 3.3

Krabbe’s disease, infantile type with caudate calciﬁca- tion

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Farina L, Bizzi A, Finocchiro G, et al (2000) MR imaging and proton MR spectroscopy in adult Krabbe disease. AJNR Am J Neuroradiol 21:1478–1482

Farley TJ, Ketonen LM, Bodensteiner JB, Wang DD (1992) Ser- ial MRI and CT ﬁndings in infantile Krabbe disease. Pedi- atr Neurol 6:455–458

Given CA 2nd, Santos CC, Durden DD (2001) Intracranial and spinal MR imaging ﬁndings associated with Krabbe’s disease. ANJR Am J Neuroradiol 22:1782–1785

Zariﬁ MK, Tzika AA, Astrakas LG, Poussaint TY, Anthony DC, Darras BT (2001) Magnetic resonance spectroscopy and magnetic resonance imaging ﬁndings in Krabbe’s disease.

J Child Neurol 16:522–526

Mucopolysaccharidoses (MPS)

Hurler-Scheie Syndrome with Prominent Virchow-Robin Spaces (MPS I H/S) Clinical Presentation

A 5-year-old male with known MPS I presents for MRI with headaches.

A. T2-weighted image shows characteristic dilated Virchow-Robin perivascular spaces, where mucopolysaccharides accumulate in phagocytic cells.

They are characteristically seen in the peritrigonal region and corpus callosum (arrows)

Figure 3.4

Hurler-Scheie syndrome with prominent Virchow-Robin spaces

A B C

D E

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B. The dilated perivascular spaces are hypointense on T1-weighted image (arrows)

C. The perivascular spaces on the corpus callosum follow the CSF signal on FLAIR image. The peritrigonal perivascular spaces range from low to isointense to CSF

D. The wide perivascular spaces on the corpus callo- sum are hypointense on DW image (arrow) E. On ADC map the perivascular spaces are hyperin-

tense

Hurler-Scheie Syndrome with Atrophy (MPS I H/S) Clinical Presentation

A 22-year-old female who presents with cord compression symptoms. She has normal intelligence (see also Chapter 10).

A. Sagittal T1-weighted image shows dilated ventricles. Note the signiﬁcantly narrowed upper spinal canal and cord compression. For more details see Chapter 10 (Spine)

B. T2-weighted image shows honeycomb appearance of the thalami (arrows). Ventriculomegaly is pres- ent with prominent sylvian ﬁssures. Dilated peritrigonal Virchow-Robin spaces are also present.

Both frontal lobes show ﬁne network of signal abnormality

C. T2-weighted image. Prominent perivascular spaces are seen throughout the white matter, the frontal lobes being the least involved

D. FLAIR image demonstrates better the thalamic abnormalities

E. FLAIR image shows periventricular white matter hyperintensities

F. Contrast-enhanced T1-weighted image fails to demonstrate enhancement in the thalamic cribriform lesions

G. DW image shows hypointensity in the thalami consistent with increased diffusibility

H. The ﬁne white matter changes and prominent perivascular space in the frontoparietal area are difﬁcult to appreciate on DW image

I. On ADC map the thalami show hyperintensity;

there is no restricted diffusion

J. Exponential image reveals hypointensity in the thalami, consistent with increased diffusion

Figure 3.5 A

Hurler-Scheie syndrome with atrophy A

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Figure 3.5 B–J

Hurler-Scheie syndrome with atrophy

B C D

E F G

H I J

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Sanﬁlippo Syndrome (MPS III) Clinical Presentation

A 6-year-old female with Sanﬁlippo syndrome has been stable and interacting until 5months ago, when she experienced a rapid downhill course. Now she is in a vegetative state with posturing.

A. Axial T2-weighted image through the cerebellum is normal

B. T2 image through the basal ganglia shows lack of myelination in the anterior limb of the internal capsule with poor myelination of the posterior limb. Normal basal ganglia structures are not identiﬁed as separate structures. There is diffuse periventricular and subcortical white matter T2 hyperintensity, and also there is low volume of white matter, thin corpus callosum and cortical volume loss with deep gyri

C and D.No abnormality is seen in the DW images

Figure 3.6

Sanﬁlippo syndrome

A B

C D

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Discussion

MPS are inherited metabolic disorders due to deficiency of lysosomal enzymes involved in the degeneration of glycosaminoglycans. Undegraded glycosaminoglycans accumulate in lysosomes and affect tissue function. MPS have been divided into seven major types. The classification is based on the deficient enzyme responsible for the disease. They share many clinical features, including multiple system involvement, organomegaly, dysostosis multiplex, facial abnormalities (“gargoylism”, coarse faces), hearing and vision loss, joint involvement, cardiac involvement and central nervous system involvement.

Profound mental retardation may be found in Hurler, Hunter’s and Sanﬁlippo syndromes (MPS types I, II, and III), but normal intellect may be retained in other MPS. All MPS have autosomal recessive inheritance, except of MPS II which is X-linked.

Imaging ﬁndings of the brain in the MPS include delayed myelination, atrophy, varying degrees of hydrocephalus, and white matter changes. The white matter and corpus callosum show a cribriform appearance due to dilated perivascular spaces ﬁlled with glycosaminoglycans (mucopolysaccharides)

Hurler Syndrome (MPS I) Hurler syndrome is characterized by deficiency of alpha-iduronidase leading to the storage and massive excretion of dermatan sulfate and heparin sulfate. In addition to the imaging findings of brain parenchyma mentioned above, progressive white matter involvement may be seen in Hurler syndrome. It may be differentiated into three different subtypes based on age at onset and severity of the clinical symptoms. The natural history of white matter abnormalities in patients with MPS is still un- clear. It has been suggested that the degree of MR changes in patients with MPS does not always reflect their neurological impairment.

Hurler-Scheie Syndrome (MPS I H/S) Hurler-Scheie syndrome represents an intermediate variant of the previous MPS type I syndrome with clinical symptoms manifesting between 3 and 8years of age. Most patients have normal or near-normal intelligence.

Cervical spinal cord compression is a typical feature.

Most patients survive to adulthood.

Hunter’s Syndrome (MPS II) Hunter’s syndrome is due to deﬁciency of iduronate 2-sulfatase enzyme.

These children tend to have severe mental retardation and deafness. Communicating hydrocephalus is common. MR studies typically demonstrate thick- ened dura, cortical atrophy, and perivascular “pits”, seen as low and high signal cystic foci on T1- and T2- weighted images.

Sanfilippo Syndrome (MPS III) Sanfilippo syndrome (MPS III), is characterized by lysosomal accumulation of the glycosaminoglycan (GAG) heparan sulfate (HS). In humans, the disease manifests in early childhood with severe developmental retardation, and is characterized by a combination of progressive mental deterioration from the third year of life, he- patosplenomegaly and a typical facial appearance (mild ‘Hurler’ phenotype), leading to death in the second decade. MR imaging shows white matter abnormalities, cortical atrophy and ventricular enlarge- ment, while other findings may include thickening of the diploë, callosal atrophy, and basal ganglia involvement. Cerebellar changes have also been described. Atrophy and abnormal or delayed myelination have been described to precede the onset of overt neurological symptoms.

Sly Disease (MPS VII) Sly disease is caused by deﬁ- ciency of beta-glucuronidase enzyme. Progressive hearing loss leading to early deafness is a prominent feature of this disease. On imaging, odontoid hypoplasia is the distinct feature.

Barone R, Nigro F, Triulzi F, Masumeci S, Fiumara A, Pavone L (1999) Clinical and neuroradiological follow-up in mucopolysaccharidosis type III (Sanﬁlippo syndrome). Neu- ropediatrics 5:270–274

Barone R, Parano E, Triﬁletti RR, Fiumara A, Pavone P (2002) White matter changes mimicking a leukodystrophy in a patient with mucopolysaccharidosis: characterization by MRI. J Neurol Sci 195:171–175

Lee C, Dineen TE, Brack M, Kirsch JE, Runge VM (1993) The mucopolysaccharidoses: characterization by cranial MR imaging. AJNR Am J Neuroradiol 14:1285–1292

Parsons VJ, Hughes DG, Wraith JE (1996) Magnetic resonance imaging of the brain, neck and cervical spine in mild Hunter’s syndrome (mucopolysaccharidoses type II). Clin Radiol 51:719–723

Zafeiriou DI, Augoustidou-Savvopoulou P, Papadopoulou FA, et al (1998) MRI ﬁndings in mild mucopolysaccharidosis II (Hunter’s syndrome). Eur J Paediatr Neurol 2:153–156

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Zellweger Syndrome Clinical Presentation

A 4-week old female infant presents with hypotonia and seizures. She also has pulmonary hypertension and multiple cysts in the kidneys.

A. Sagittal T1-weighted image reveals underdevelop- ment of the rostrum and genu of the corpus callo- sum (arrow)

B. T2-weighted image shows paucity of cortical gyri that appear broad as seen in pachygyria. The cortex is thick, especially in the frontal and temporal regions. No myelination is seen in the corticospinal tracts

Figure 3.7

Zellweger syndrome

A B

C D E

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C. T2-weighted image. Polymicrogyria are seen in the poorly developed sylvian ﬁssure regions (ar- rows). There are no germinolytic cysts

D. The cortex reveals also broad and shallow gyri on T2-weighted image. Low volume of white matter is seen in the centrum semiovale. There is lack of myelination in the motor cortex that is usually myelinated at birth

E. No signal abnormality is seen on DW image

Discussion

Zellweger (cerebrohepatorenal) syndrome is a rare, congenital disorder characterized by the reduction or absence of peroxisomes that presents in the neonatal period. Patients are characterized by multiple distur- bances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct facial dysmorphism and malformations in the brain. Additional features include mental retardation, liver dysfunction and renal cysts. The disorder is always fatal and most patients die within the ﬁrst year.

MR imaging is the neuroimaging study of choice.

MR imaging demonstrates the unusual combination of abnormalities of neuronal migration disorders with heterotopic gray matter, pachygyria, polymicrogyria, with hypomyelination. Abnormal gyration is most commonly seen in the perisylvian and periro- landic regions. Some authors consider the cortical changes as cortical dysplasia rather than true migration anomaly. Nonspeciﬁc subependymal germinolytic cysts may be seen as a result of hemorrhage.

The presence of hypomyelination helps in differentiating Zellweger syndrome from neonatal adrenoleukodystrophy. Congenital muscular dystrophies can be differentiating from Zellweger syndrome by absence of facial deformities, seizures and lack of hypotonia.

Barkovich AJ, Peck WW (1997) MR of Zellweger syndrome.

AJNR Am J Neuroradiol 18:1163–1170

Pueschel SM, Oyer CE (1995) Cerebrohepatorenal (Zellweger) syndrome: clinical, neuropathological, and biochemical ﬁndings. Childs Nerv Syst 11:639–642

Adrenoleukodystrophy Clinical Presentation

A 21-month-old male with a history of myopathy.

Image (Fig. 3.8)

A. T2-weighted image shows extensive peritrigonal demyelination with lesser areas of demyelination in the deep white matter anteriorly and around the frontal horns

Discussion

Adrenoleukodystrophy is a rare genetic metabolic disorder characterized by progressive demyelination of nerve cells in the brain, dysfunction of adrenal glands and testes due to impaired peroxisomal function. Adrenoleukodystrophy comprises three subtypes: X-linked recessive disorder, and neonatal and childhood forms. In adrenoleukodystrophy, there is accumulation of high levels of very long-chain fatty acids in various organs due to the absence of peroxisomes. This accumulation is most severe in the brain and adrenal glands resulting in neurological prob- lems and endocrine dysfunction. Neonatal adreno-

Figure 3.8

Adrenoleukodystrophy

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leukodystrophy presents with mental retardation, facial abnormalities, retinal degeneration, weak muscle tone, enlarged liver, and adrenal dysfunction. This form usually progresses rapidly. Neonatal adrenoleukodystrophy is similar to Zellweger syndrome and may actually represent a milder variant of Zellweger syndrome. Neonatal adrenoleukodystrophy has de- myelinating with inﬂammatory cells and foamy mi- crophages whereas Zellweger syndrome patients have hypomyelination.

On T2-weighted MR images, bilateral symmetrical diffuse deep white matter high signal foci are seen in the occipital lobes. A bilateral occipital pattern with involvement of pontomedullary corticospinal tracts is an extremely helpful ﬁnding in the diagnosis of adrenoleukodystrophy. Contrast enhancement may be seen and is attributed to the inﬂammatory process.

Barkovich AJ, Ferriero DM, Bass N, Boyer R (1997) Involve- ment of the pontomedullary corticospinal tracts: a useful ﬁnding in the diagnosis of X-linked adrenoleukodystrophy. AJNR Am J Neuroradiol 18:95–100

Chen X, DeLellis RA, Hoda SA (2003) Adrenoleukodystrophy.

Arch Pathol Lab Med 127:119–120

Melhem ER, Gotwald TF, Itoh R, Zinreich SJ, Moser HW (2001) T2 relaxation measurements in X-linked adrenoleukodystrophy performed using dual-echo fast ﬂuid-attenuated inversion recovery MR imaging. AJNR Am J Neuroradiol 22:773–776

Neuronal Ceroid Lipofuscinosis (NCL)

Juvenile NCL with Mild Radiographic Changes Clinical Presentation

A 14-year-old male with juvenile NCL (Spielmeyer- Vogt subtype) with seizures, developmental delay and progressive mental deterioration. He has also von Willebrand’s disease.

A. T2-weighted image at the age of 14years shows only mild volume loss. The thalami show hypointensity, except the posterior, medial aspect.

The putamen also shows hypointensity and is isointense with the globus pallidus’ normal low signal

B. CT scan at the age of 19years shows signiﬁcant progression of the global atrophy with dilated ventricles and cortical sulci. Note traumatic changes in the subcutaneous tissue on the left

Figure 3.9

Juvenile neuronal ceroid lipofuscinosis with mild radiographic changes

A B

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Juvenile NCL with Atrophy Clinical Presentation

A 15-year-old female with seizures, progressive visual loss and developmental delay. She has juvenile or Spielmeyer-Vogt subtype of NCL.

A. Sagittal T1-weighted image shows severe cerebellar atrophy

B. T2-weighted image conﬁrms the presence of cerebellar atrophy

C. T2-weighted image through the superior cerebellar peduncles shows signiﬁcant atrophy

D. T2-weighted image through the basal ganglia shows hypointensity in the putamen with a thin linear hypointensity in both thalami. External capsule shows hyperintensity consistent with demyelination or gliosis

E. Cortical brain atrophy is present on T2-weighted image

F. MRS (TE=35ms) shows decreased NAA peak with increased myoinositol peak. Cho and Cr peaks are normal

Discussion

NCL represent a group of inherited neurodegenerative disorders with an autosomal recessive inheritance. They are caused by the accumulation of lipopigment within the lysosomes of neurons and other tissues. Several main types have been described: infantile onset (Haltia-Santavuori subtype), late infantile (Jansky-Bielschowsky subtype), and juvenile (Spielmeyer-Vogt or Batten subtype), to adult onset (Kufs subtype) forms, and early juvenile and heterogeneous group atypical forms. The most common types are the infantile and classic juvenile forms. Infantile NCL is progressive and uniformly fatal. The common clinical presentation is seizures, delayed milestones leading to dementia, involuntary movements, ataxia, visual loss and abnormal behav- ior.

In the infantile type the typical MR imaging ﬁnd- ings can be seen even before the clinical signs. In the classic late infantile type, MR imaging is less inform- ative in the early phase. When the disease progresses MR imaging demonstrates global cerebral and cerebellar atrophy, T2-hyperintensity of the lobar white matter and thinning of the cerebral cortex. Hy- pointensity is seen in the thalami. MR spectroscopy shows reduction of NAA consistent with neuronal damage. An increase of myoinositol and glutamine/

glutamate is seen. No lactate is seen, helping in MR imaging differentiation between this disease and the mitochondrial group. The infantile type shows early atrophy and decreased signal in the thalami. A periventricular high-signal rim on T2-weighted MR images is a typical ﬁnding. Hypointensity is seen in addition to the thalami also in the corpus striatum.

Atrophy, most prominent in the cerebellum, is especially marked in the infantile and late infantile subtypes. Demyelination and gliosis may be seen initially in the external capsules, but later in the cerebral white matter. An autopsy MR imaging correlation study has shown that periventricular changes detect- ed in vivo on MRI are due to severe loss of myelin and gliosis. MR spectroscopy shows reduced levels of NAA.

Autti T, Raininko R, Santavuori P, Vanhanen SL, Poutanen VP, Haltia M (1997) MRI of neuronal ceroid lipofuscinosis. II.

Postmortem MRI and histopathological study of the brain in 16 cases of neuronal ceroid lipofuscinosis of juvenile or late infantile type. Neuroradiology 5:371–377

D’Incerti L (2000) MRI in neuronal ceroid lipofuscinosis. Neu- rol Sci 21:71–73

Santavuori P, Vanhanen SL, Autti T (2001) Clinical and neuroradiological diagnostic aspects of neuronal ceroid lipofuscinosis disorders. Eur J Paediatr Neurol [Suppl A]:157–161 Vanhanen SL, Raininko R, Santavuori P (1994) Early differen- tial diagnosis of infantile neuronal ceroid lipofuscinosis, Rett syndrome, and Krabbe disease by CT and MR. AJNR Am J Neuroradiol 15:1443–1453

Vanhanen SL, Raininko R, Autti T, Santavuori P (1995) MRI evaluation of the brain in infantile neuronal ceroid-lipofuscinosis, part 2. MRI ﬁndings in 21 patients. J Child Neu- rol 10:444–450

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Figure 3.10

Juvenile neuronal ceroid lipofuscinosis with atrophy

A B

C

F

D E

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Mitochondrial Disorders MELAS at Six Days of Age Clinical Presentation

A 6-day-old female infant with lactic acidosis.

A. T2-weighted image is unremarkable

B. MRS (TE=135ms) shows reversed lactate peak at 1.3ppm. The low NAA and high Cho peaks are normal for a 6-day-old infant

Figure 3.11

MELAS at 6 days of age

A B

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MELAS at Twenty Months of Age Clinical Presentation

A 20-month-old female with lactic acidosis, developmental delay and seizures.

A. There is increased signal on T2-weighted images diffusely within the cortex of both cerebral hemispheres, within the subcortical white matter bilaterally and also within the basal ganglia, cingular gyrus and thalami bilaterally. Diffuse mass effect upon the sulci is present

B. Coronal FLAIR shows hyperintensity involving both hemispheres and thalami compared to the darker (normal) signal in the cerebellum

C. DW image reveals increased signal in both cere- bral hemispheres (arrows), cingular gyri and on both thalami

D. MR spectroscopy (TE=135ms). Single voxel was placed over the subcortical and deep white matter in the right parietal region. There is an inverted lactate peak at 1.3ppm consistent with increased anaerobic glycolysis. The NAA peak is signiﬁcant- ly decreased with normal Cr and Cho peaks

Figure 3.12

MELAS at 20 months of age A

D

B C

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Kearns-Sayre Syndrome Clinical Presentation

A young adult who has profound deafness since late teens, dementia, ataxia, and ophthalmoplegia.

A. T2-weighted image through basal ganglia shows subcortical white matter hyperintensity sparing the corpus callosum and optic radiation. The globus pallidi show round hyperintensity bilater- ally (arrows)

B. T2-weighted image through the centrum semiovale shows the peripheral “new” subcortical white matter involvement sparing the central “older”

white matter

Figure 3.13

Kearns-Sayre syndrome

A B

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Leigh’s Disease, Classic Presentation Clinical Presentation

A 2-year-old female with failure to thrive.

A. Noncontrast CT image shows low densities in the caudate and lentiform nuclei (arrows)

B. T2-weighted image demonstrates increased signal within the lentiform nucleus and caudate nuclei bilaterally (arrows)

C. T1-weighted image shows low signal in the cau- date and lentiform nucleus (arrows)

D. Contrast-enhanced T1-weighted image shows no abnormal contrast enhancement

Figure 3.14

Leigh’s disease, classic presentation

A B

C D

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Leigh’s Disease, Classic Presentation with Cerebellar Involvement

Clinical Presentation

A 3-year-old male with arrested development, trun- cal ataxia and nystagmus since the age of 19months.

He presents with respiratory failure.

A. T2-weighted image shows increased signal within the caudate nuclei and putamen bilaterally (ar- rows)

B. The hyperintense areas are better seen on axial FLAIR image (arrows)

C. Coronal FLAIR image reveals hyperintense lesions symmetrically and diffusely also within the cere- bellar hemispheres (arrows)

Leigh’s Disease, Peripheral Involvement Clinical Presentation

An 18-year-old female college student with new onset of seizures. She had repeatedly high lactate in the CSF. Brain biopsy was obtained.

A. T2-weighted image shows hyperintense lesion in the left posterior temporal and parietal region (ar- row). Another T2 hyperintensity is seen in the pe- riaqueductal gray matter (arrowhead)

B. DW image shows hyperintensity in the same lesions

C. ADC map shows increased signal in the left posterior temporoparietal and periaqueductal areas D. There was no enhancement in the abnormal areas E. MR spectroscopy (TE=35ms) from left temporal lesion. Although the image is noisy, it demonstrates the presence of lactate at 1.33ppm

F. MR spectroscopy (TE=144ms) from the same area as in E demonstrates an inverted lactate doublet at 1.33ppm

Figure 3.15

Leigh’s disease, classic presentation with cerebellar involvement

A B C

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Figure 3.16

Leigh’s disease, peripheral involvement

A B C

D E

F

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Discussion

Mitochondrial disorders are a clinically heterogeneous group of diseases caused by defects in mitochondrial function and oxidative phosphorylation.

The most common disorder is MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like events) which is a multisystem disease associated with specific maternally inherited point mutations of mitochondrial DNA (mtDNA). The most common of these is an A-to-G transition at nucleotide 3243 of the tRNA Leu (UUR) gene. This point mutation is hetero- plasmic, i.e. both normal and mutant mtDNA coexist in the tissues of the patient and the clinical symptoms are often related to the proportion of mutant and normal mtDNA in different tissues. The high energy demand of brain and muscle makes them particularly vulnerable to deficient energy production. MELAS is characterized by stroke-like episodes often preced- ed by treatment-resistant partial seizures. Short stature, diabetes mellitus, and slowly progressive mental impairment leading to dementia are common features. Exercise intolerance is common. Histologi- cal examination and muscle biopsy reveals accumulation of abnormal mitochondria and ragged red fibers.

During stroke-like episodes, CT and MR imaging reveal multifocal infarct-like, mainly gray matter lesions, not conﬁned to the vascular territories. MR imaging classically demonstrate signal changes involving both grey and white matter predominantly in the occipital and parietal lobes that strongly mimic stroke lesions. DW imaging shows increased ADC values consistent with predominant extracellular edema in acute lesions in MELAS thereby indicating a nonischemic cause of the strokes seen in MELAS.

MR spectroscopy may show lactate peaks suggestive of metabolic damage associated with this disease.

Leigh’s syndrome, also known as subacute necrotizing encephalomyelopathy, is included with mitochondrial cytopathies. It is a progressive neurodegenerative disorder associated with several enzyme deﬁciencies such as pyruvate dehydrogenase com- plex, pyruvate carboxylase and defects in electron transport chain. Leigh syndromes have a common clinical phenotype, although genetic and biochemical abnormalities are heterogeneous. They are characterized by spongiosis, astrogliosis and capillary proliferation. Three clinical subtypes are identiﬁed:

infantile type with symptoms occurring in ﬁrst 2years of life, juvenile form and adult form. The infantile form presents with hypotonia, vomiting, seizures, and death from respiratory failure. On CT

images, non-enhancing hypodense areas are seen in the putamen and caudate nuclei. In the classic form T2-weighted MR images show symmetric hyperintense foci in the globus pallidus, putamen, and caudate nuclei. Putaminal involvement is not a pathog- nomonic radiological ﬁnding. The brain stem tegmentum, particularly the mesencephalon, is characteristically involved on MR imaging in the early and late phases of the illness. Patients who harbor ap- proximately 70–90% mutant mtDNA in their tissues have highly variable manifestations. Patients with over 90% mutations have severe disease, such as Leigh’s disease.

Kearns-Sayre syndrome is an autosomal domi- nant mitochondrial encephalopathy caused by dele- tion in muscle mtDNA with elevated serum pyruvate.

Clinical features include progressive ophthalmoplegia, pigmentary degeneration of the retina, ataxia, myopathy, and cardiac conduction defects. On MR imaging, T2-weighted images show high signal intensity areas in the brain stem, globus pallidus, thalamus, and white matter of the cerebrum and cerebellum.

The peripheral (“new”) white matter is involved sparing the deep (“old”) white matter. The imaging ﬁnd- ings may be similar to those seen in Leigh’s disease.

Abe K, Yoshimura H, Tanaka H, Fujita N, Hikita T, Sakoda S (2004) Comparison of conventional and diffusion-weighted MRI and proton MR spectroscopy in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like events. Neuroradiology 46:113–117

Arii J, Tanabe Y (2000) Leigh syndrome: serial MR imaging and clinical follow-up. AJNR Am J Neuroradiol 21:1502–1509 Heckmann JM, Eastman R, Handler L, Wright M, Owen P

(1993) Leigh disease (subacute necrotizing encephalomyelopathy): MR documentation of the evolution of an acute attack. AJNR Am J Neuroradiol 14:1157–1159 Phillips CI, Gosden CM (1991) Leber’s hereditary optic neu-

ropathy and Kearns-Sayre syndrome: mitochondrial DNA mutations. Surv Ophthalmol 35:463–472

Schoffner JM (1996) Maternal inheritance and the evaluation of oxidative phosphorylation diseases. Lancet 348:1283–

1288

Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H (1998) Neuroradiological ﬁndings in children with mitochondrial disorders. AJNR Am J Neuroradiol 19:369–377 Yonemura K, Hasegawa Y, Kimura K, Minematsu K, Yamaguchi

T (2001) Diffusion-weighted MR imaging in a case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes. AJNR Am J Neuroradiol 22:269–272 Zeviani M, Moraes CT, DiMauro S, et al (1988) Deletions of mi-

tochondrial DNA in Kearns-Sayre syndrome. Neurology 38:1339–1346

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Cerebellar Degeneration Associated with Coenzyme Q10 Deﬁciency Clinical Presentation

An 8-year-old male with episodic seizures and ataxia.

A. Axial T2-weighted image through posterior fossa shows marked atrophy of cerebellum with abnor- mal hyperintensity (arrows)

B. Sagittal T1-weighted image also shows cerebellar atrophy

C. Coronal FLAIR shows signiﬁcant cerebellar cortical hyperintensity with normal-appearing white matter (arrows)

D. Axial contrast-enhanced T1-weighted image shows no signiﬁcant enhancement in the cerebellum E. Coronal contrast-enhanced gradient echo (SPGR)

image reveals cortical low signal intensity in the cerebellum (arrows). No abnormal enhancement is present

F. DW image through posterior fossa shows no sig- niﬁcant abnormality

Figure 3.17

Cerebellar degeneration associated with coenzyme Q10 deﬁciency

A B C

D E F

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Discussion

Coenzyme Q10 is an essential lipophilic component of an electron transport chain that has oxidoreduc- tase functions. It also serves as an antioxidant and membrane stabilizer and has been found to protect cultured cerebellar neurons against both spontaneous and toxin-induced degeneration.

Primary coenzyme Q10 deficiency is a mitochondrial encephalopathy with a heterogeneous clinical presentation. It was first reported as a predominantly myopathic form in two sisters in 1989 characterized by the triad of exercise intolerance, recurrent myo- globinuria, and neurological manifestations. Howev- er, the most frequent ataxic form is dominated by ataxia and cerebellar atrophy, and is variously associated with seizures, developmental delay, weakness, pyramidal signs, or peripheral neuropathy. A third less-common form with fatal infantile encephalomyopathy and renal involvement has also been described. Usually the presentation is in childhood, but sometimes it may be delayed in onset until even fifth decade of life.

On imaging, atrophy of the cerebellar hemispheres as well as the vermis is the hallmark of primary CoQ10 deﬁciency. MR imaging is the modality of choice to demonstrate such atrophy. Primary coenzyme Q10 deﬁciency is important to diagnose, as its clinical spectrum continues to expand and more im- portantly such patients may improve with early ad- ministration of CoQ10 supplementation.

Favit A, Nicoletti F, Scapagnini U, Canonico PL (1992) Ubi- quinone protects cultured neurons against spontaneous and excitotoxin-induced degeneration. J Cereb Blood Flow Metab 12:638–645

Gironi M, Lamperti C, Nemmi R, et al (2004) Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deﬁciency. Neurology 62(5):818–820

Lamperti C, Naini A, Hirano M, et al (2003) Cerebellar ataxia and coenzyme Q10 deﬁciency. Neurology 60:1206–1208 Musumeci O, Naini A, Slonim AE, et al (2001) Familial cerebel-

lar ataxia with muscle coenzyme Q10 deﬁciency. Neurolo- gy 56:849–855

Ogasahara S, Engel AG, Frens D, Mack D (1989) Muscle coenzyme Q deﬁciency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A 86:2379–2386

Hallervorden-Spatz Disease Clinical Presentation

A 12-year-old girl with visual symptoms and progressive spasticity and choreoathetosis.

Image (Fig. 3.18)

A. T2-weighted image shows dark signal in the globus pallidus with symmetric hyperintense foci in medial globus pallidus. This is “classical eye-of- the-tiger” imaging appearance in this entity

Figure 3.18

Hallervorden-Spatz disease, classical presentation

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Asymmetric Presentation Clinical Presentation

A 15-year-old girl with visual symptoms, dysarthria and seizures.

A. T2-weighted image shows (more than expected) low signal in the globus pallidi with a central high signal (arrows), the so called “eye-of-the-tiger”.

The high signal areas in the globus pallidi are slightly asymmetric

B. MR spectroscopy (TE=35ms) reveals decreased NAA with increased myoinositol peaks. Cho is also low

C. T2-weighted image demonstrates the voxel loca- tion over the left basal ganglia

Discussion

Hallervorden-Spatz disease (synonym: neurodegeneration with brain iron accumulation, pantothenate kinase-associated neurodegeneration) is a rare neurodegenerative disorder characterized by iron accumulation in the basal ganglia, progressive extrapyra- midal dysfunction and dementia. The exact patho- genesis is unknown. Mutations in the pantothenate kinase 2 gene (PANK2) have been shown to lead to pantothenate kinase-associated neurodegeneration by inﬂuencing mitochondrial function. This may lead to abnormal iron accumulation in the globus pallidus and reticular substantia nigra and cause late-onset neurodegenerative disorders.

Figure 3.19

Hallervorden-Spatz disease, asymmetric presentation A

C

B

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Noncontrast-enhanced CT shows bilateral low densities in the globus pallidus and substantia nigra.

T2-weighted MR images demonstrate hypointense signals due to iron accumulation. Areas of gliosis, demyelination, neuronal loss, and axonal swelling are seen as high signal intensity areas on T2-weighted MR images. Initially hyperintense areas are seen in the globus pallidi and substantia nigra. Later as the disease progresses, a hypointense rim is seen around it, due to iron deposition, causing the characteristic

“eye-of-the-tiger” sign.

Johnson MA, Kuo YM, Westaway SK, Parker SM, Ching KH, Gitschier J, Hayﬂick SJ (2004) Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. Ann N Y Acad Sci 1012:282–298

Nuri Sener R (2003) Pantothenate kinase-associated neurodegeneration: MR imaging, proton MR spectroscopy, and diffusion MR imaging ﬁndings. AJNR Am J Neuroradiol 24:1690–1693

Sethi N, Sethi PK (2003) Eye-of-the-tiger sign. J Assoc Physi- cians India 51:486

Swaiman KF (2001) Hallervorden-Spatz syndrome. Pediatr Neurol 25:102–108

Trimble M (2003) Magnetic resonance imaging and Hallervor- den-Spatz syndrome. CNS Spectr 8:420

Defects in Genes Encoding the Myelin Proteins

Pelizaeus-Merzbacher Disease Pelizaeus-Merzbacher Disease with Lack of Normal Myelination Clinical Presentation

A 10-month-old male with nystagmus and developmental delay presents for MR imaging evaluation.

Image (Fig. 3.20)

A. T2-weighted image demonstrates diffuse hyperintensity in the white matter including the corpus callosum and internal capsule. This is consistent with near-total lack of normal myelination. Severe white matter atrophy is present with normal-appearing cortical ribbon

Figure 3.20

Pelizaeus-Merzbacher disease with lack of normal myelination

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Pelizaeus-Merzbacher Disease with Delayed Myelination Clinical Presentation

An 11-month-old male with developmental delay, ataxia, visual symptoms and spasticity. He has a 3- year-old brother with similar symptoms and hypomyelination on MRI.

A. T2-weighted image fails to show myelination in posterior limbs of internal capsules (arrows) usu- ally present by 2months of age

B. Brain myelination is inappropriate for an 11- month-old, since no myelination is present on T2- weighted image

Pelizaeus-Merzbacher Disease

with Prominent Cerebellar Involvement Clinical Presentation

A 9-year-old male with developmental delay and hypotonia.

A. Noncontrast CT scan at the age of 1year shows sig- niﬁcant hypodensity in the white matter tracts B. The white matter tracts show unusual low density

also in the supratentorial area on noncontrast CT image

C. T2-weighted image at the age of 9years shows abnormal hyperintensity in the cerebellum

D. T2-weighted image fails to show any myelination in the corticospinal ﬁbers as expected. The centrum semiovale is abnormally hyperintense

Discussion

Pelizaeus-Merzbacher disease is an X-linked recessive leukodystrophy caused by a mutation in the pro- teolipid protein gene on chromosome Xq22.It is characterized by hypotonia, respiratory distress, stridor, nystagmus, and profound myelin loss. It has been divided into a number of subtypes.

Figure 3.21

Pelizaeus-Merzbacher disease with delayed myelination

A B

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On CT images, mild nonspeciﬁc cerebral and cerebellar atrophy is seen. T2-weighted MR images show extensive white matter hypomyelination. Severe cases may show near-total lack of myelination which ex- tends peripherally to involve the arcuate ﬁbers. The white matter has often a “tigroid” appearance. There is no histological evidence of demyelination. The brain stem, diencephalon, cerebellum, and subcortical white matter may show preservation of myelin.

MR spectroscopy may show decreased choline peaks in the white matter resulting in markedly high NAA/Cho ratios, and low Cho/Cr ratios representing deﬁcient myelination. Diffusional anisotropy in the corpus callosum, internal capsule and white matter of the frontal lobes has been reported.

p10 p9 Translocation Clinical Presentation

A 13-month-old female with chromosome disorder:

translocation of p10 and p9. She had abnormal pre- natal ultrasound and postnatal CT scan. She has cardiac, visceral and skeletal abnormalities, developmental delay and cleft palate.

A. Sagittal T1-weighted image demonstrates vermian hypoplasia with a prominent retrocerebellar CSF space. This CSF space communicates with the fourth ventricle (arrow). The corpus callosum is present but hypoplastic

Figure 3.22

Pelizaeus-Merzbacher disease with prominent cerebellar involvement

A B

C D

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B. Signiﬁcant areas of the periventricular white matter demonstrate an abnormal high signal on T2- weighted image (arrows). Patchy areas of abnor- mal high signal are seen also in the subcortical white matter (arrowheads). The internal capsules show normal myelination and the thin genu of the corpus callosum is myelinated

C. T2-weighted image reveals prominent extra-axial CSF space bilaterally. The falx is absent. The white matter volume is low. The centrum semiovale white matter is still abnormally bright (arrows) D. Coronal T2-weighted image demonstrates normal

myelination in the anterior limb on the internal capsules (arrows). The sylvian ﬁssures are open

Figure 3.23 p10 p9 translocation

A B

C D

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and the extra-axial CSF spaces are prominent.

There is lack of maturity of subcortical white matter. The white matter volume is also decreased. No falx is visualized

18q Syndrome Clinical Presentation

A 15-month-old male who presents with microcephaly, developmental delay and hypotonia.

A. T1-weighted image shows microcephaly, low white matter volume, abnormal gyration and lack of normal operculum formation (arrow)

B. T2-weighted image conﬁrms the ﬁndings in A. Ad- ditionally prominent perivascular spaces (arrows) are better appreciated

C. MR spectroscopy (TE=35ms) placing voxel over right centrum semiovale reveals no abnormal metabolites. Relatively low NAA reﬂects patient’s age rather than abnormality

Discussion

Leukodystrophies are a heterogeneous group of disorders that affect the central and sometimes the peripheral nervous systems and predominantly involve the white matter.A typical feature is abnormal myelin formation and/or maintenance of normal formed myelin. Although destruction is seen typically in de- myelinating diseases, this may also be seen in the leukodystrophies.

Figure 3.24 18q syndrome

A

C

B